Research Synopsis:Research interests in the Andreana Research Group include natural and natural-product-like synthesis, carbohydrate-based vaccine design and development and small molecule combinatorial methods for high-throughput screening. The key underlying question for our research program is: How do carbohydrates and small molecules modulate cellular function? In order to address this question, chemistry as the vector into biology is emphasized.

Synthesis
of Naturally Occurring Carbohydrates / Polysaccharides

One objective is to prepare well-defined zwitterionic
polysaccharides (ZPS), in which the oligosaccharide is amenable to chemical
modifications for the development of bioprobes. The long term goal is to elucidate a better under-standing
of how these synthesized molecules illicit immune responses
presumably via the MHCII pathway.

Carbohydrate-Based,
Diversity Oriented Synthesis

Another
objective in our group is to examine a diversity oriented synthesis (DOS)
approach toward the construction of a class of compounds containing
carbohydrate scaffolds as potential therapeutic agents. DOS is enabling
because it provides a platform for fast and facile modifications of carbon
skeleton frameworks.

Carbohydrate-Based
Vaccines

Current
carbohydrate-based vaccines, while effective, do not protect against the
carrier protein and, therefore, an
immunogenic response is heterogen-eous in nature. Our
objective is to prepare well-known carbohydrate antigens, such as the well-defined tumor motifs, bacterial polysaccharides and those
found on viral capsids (Man9GlcNAc2- HIV gp120). Our approach entails synthe-sizing oligosaccharides that are
then linked to a T-cell inducing ZPS (such as PS A1) for the development
of carbohydrate-based vaccines.

To understand molecular structure and function pertaining
to biological systems, the Andreana group will take advantage of solid support,
split-pool concept of combinatorial chemistry and
develop carbohydrate-based libraries. For example, it is of great interest
to determine, systematically, how the electrostatic charges of ZPSs interact
with various modulators of immune cells.

Small Molecule Synthesis (Green
Chemistry)

Our small molecule synthesis program
ties in with a platform for the development of modulators (Chemical Genetics)
of the immune pathway to determine mechanistic insights of carbohydrate
processing in the antigen presenting cell or dendrite cell. For example, the
tyrosine kinase p56 (lck) is present in T-cells and is known to be required to
initiate the activation response from the T-cell receptor (TCR) intracellular
domain to other signaling proteins. T-cells that lack lck are unable to respond
to stimulation through the TCR.

Rational Drug Design Targeting
Tuberculosis

In the past several decades, there has been an emergence
of increasingly drug-resistant strains of TB bacteria. Multi-drug-resistance
(MDR) TB is a major concern as at least 2 of the best anti-TB
drugs: isoniazid and rifampin
are rendered ineffective. In under-standing biosynthetic pathways and en-zymatic mechanisms, synthetic sub-strates
in conjunction with rationally designed inhibitors will be used to target
essential enzymes known for the survival of TB.